Parkin regulates translesion DNA synthesis in response to UV radiation.
Parkin regulates translesion DNA synthesis in response to UV radiation.
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Parkin 调节跨损伤 DNA 合成以响应紫外线辐射
DOI：
10.18632/oncotarget.16855
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发表时间：
2017-05-30
期刊：
影响因子：
--
通讯作者：
Tang TS
中科院分区：
文献类型：
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作者：
Zhu X;Ma X;Tu Y;Huang M;Liu H;Wang F;Gong J;Wang J;Li X;Chen Q;Shen H;Zhu S;Wang Y;Liu Y;Guo C;Tang TS
帕金森缺乏是早发性帕金森病(PD)的主要原因。值得注意的是，帕金森病患者在黑色素瘤和其他皮肤肿瘤中也表现出显著更高的风险，而其机制在很大程度上仍不清楚。在这项研究中，我们证明了在紫外线(UV)辐射后，Parkin的枯竭会导致细胞活性和基因组稳定性的下降。我们证明，Parkin通过促进紫外光照射下复制蛋白A(RPA)包被的单链DNA的形成，促进了高效的依赖于Rad18的增殖细胞核抗原(PCNA)的单泛素化。此外，帕金被发现与NBS1(奈梅根断裂综合征1)存在物理上的相互作用，并且对于NBS1和DNA聚合酶ETA(POLη)在紫外线诱导的损伤部位的最佳募集是必需的。因此，Parkin的耗尽会导致紫外线诱导的突变增加。这些发现揭示了Parkin在保护基因组稳定性方面的重要作用，它通过积极调节紫外线损伤下的跨病变DNA合成(TLS)，提供了Parkin缺陷与PD患者皮肤癌易感性之间的新的机制联系。
Deficiency of Parkin is a major cause of early-onset Parkinson's disease (PD). Notably, PD patients also exhibit a significantly higher risk in melanoma and other skin tumors, while the mechanism remains largely unknown. In this study, we show that depletion of Parkin causes compromised cell viability and genome stability after ultraviolet (UV) radiation. We demonstrate that Parkin promotes efficient Rad18-dependent proliferating cell nuclear antigen (PCNA) monoubiquitination by facilitating the formation of Replication protein A (RPA)-coated ssDNA upon UV radiation. Furthermore, Parkin is found to physically interact with NBS1 (Nijmegen breakage syndrome 1), and to be required for optimal recruitment of NBS1 and DNA polymerase eta (Polη) to UV-induced damage sites. Consequently, depletion of Parkin leads to increased UV-induced mutagenesis. These findings unveil an important role of Parkin in protecting genome stability through positively regulating translesion DNA synthesis (TLS) upon UV damage, providing a novel mechanistic link between Parkin deficiency and predisposition to skin cancers in PD patients.